Hydrochloric Acid → cis-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate

HRID 1963468노트

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HRID 1963468 반응식
[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH:17]([C:19]([OH:21])=O)[CH2:16][CH2:15][N:14]2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:38]([O:40][C:41](=[O:46])[CH2:42][C:43]([O-:45])=O)[CH3:39].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O.CC(OC)(C)C>[F:12][C:6]1[CH:5]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19](=[O:21])[CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:46])[CH2:16][CH2:15][N:14]2[C:22]([O:24][CH3:25])=[O:23])[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:10])([F:9])[F:11].[F:12][C:6]1[CH:5]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:43](=[O:45])[CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:46])[CH2:16][CH2:15][N:14]2[C:22]([O:24][CH3:25])=[O:23])[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:11])([F:9])[F:10]

참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667321922-(3,5-Difluoro-4-(trifluoromethyl)phenyl)-1-(methoxy-carbonyl)piperidine-4-carboxylic acid2회

생성물 2

HCID 131730427cis-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate수율 52.9%HCID 131730428trans-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate수율 3.91%

시약·촉매·용매 3

HCID 962Water용매HCID 15413tert-Butyl methyl ether용매HCID 178479889HCID 178479889, 화합물용매2회

실험 절차

2-(3,5-Difluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.363 g, 6.43 mmol) (reference compound 30) was dissolved in methyl THF (30 mL) and di(1H-imidazol-1-yl)methanone (1.565 g, 9.65 mmol) added. The suspension was stirred at room temperature under nitrogen for 20 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.190 g, 12.87 mmol) and magnesium chloride (1.225 g, 12.87 mmol) were suspended in methyl THF (30.0 mL) and stirred with an oversized stirring bar at 50° C. under nitrogen for 20 h (flask 2). The white suspension in flask 2 was then added to flask 1. The thick white suspension was stirred at room temperature for 24 h. The reaction mixture was acidified by addition of 3 M HCl to pH 1. MTBE (250 mL) and water were added, shaken and the phases separated. The organic phase was washed with water (200 mL), satd NaHCO3 (200 mL), brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 40% EtOAc in heptane over 2 CV followed by 40% to 80% of EtOAc in heptane over 10 CV was used as mobile phase. Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.489 g, 52.9%) and trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.110 g, 3.91%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.25 (t, 3H), 1.49-2.28 (m, 4H), 2.80-2.91 (m, 1H), 3.23-3.31 (m, 1H), 3.44 (s, 2H), 3.65 (s, 3H), 4.07-4.14 (m, 1H), 4.17 (q, 2H), 4.86-4.95 (m, 1H), 6.83 (d, 2H). Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.24 (t, 3H), 1.54-1.60 (m, 1H), 1.73-1.89 (m, 1H), 1.96-2.03 (m, 1H), 2.38-2.47 (m, 1H), 2.53-2.62 (m, 1H), 2.76-2.84 (m, 1H), 3.40-3.49 (m, 2H), 3.75 (s, 3H), 4.17 (q, 2H), 4.15-4.42 (m, 1H), 5.40-5.71 (m, 1H), 6.87 (d, 2H).

후처리

  1. stirringstirred with an oversized stirring bar at 50° C. under nitrogen for 20 h (flask 2)
  2. additionThe white suspension in flask 2 was then added to flask 1
  3. stirringThe thick white suspension was stirred at room temperature for 24 h
  4. stirringshaken
  5. customthe phases separated
  6. washThe organic phase was washed with water (200 mL), satd NaHCO3 (200 mL), brine (200 mL)
  7. customdried with a phase separator
  8. customevaporated in vacuo
  9. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column

출처 및 근거

ORD 기록
ord-e63cc200b15a49b3bbe1f31fff87f1a6
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08415378B2

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